α-synuclein impairs autophagosome maturation through abnormal actin stabilization

Vesicular trafficking defects, particularly those in the autophagolysosomal system, have been strongly implicated in the pathogenesis of Parkinson's disease and related α-synucleinopathies. However, mechanisms mediating dysfunction of membrane trafficking remain incompletely understood. Using a...

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Bibliographic Details
Published in:PLoS genetics 2021-02, Vol.17 (2), p.e1009359
Main Authors: Sarkar, Souvarish, Olsen, Abby L, Sygnecka, Katja, Lohr, Kelly M, Feany, Mel B
Format: Article
Language:English
Subjects:
Actin
Age
Antibodies
Autophagy
Biology and Life Sciences
Cytoskeleton
Disease
Engineering and Technology
Genotype & phenotype
Insects
Kinases
Medicine and Health Sciences
Mitochondria
Movement disorders
Mutation
Neurodegeneration
Neurodegenerative diseases
Parkinson's disease
Pathogenesis
Proteins
Quantitative analysis
Research and Analysis Methods
Spectrin
Synuclein
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Summary:Vesicular trafficking defects, particularly those in the autophagolysosomal system, have been strongly implicated in the pathogenesis of Parkinson's disease and related α-synucleinopathies. However, mechanisms mediating dysfunction of membrane trafficking remain incompletely understood. Using a Drosophila model of α-synuclein neurotoxicity with widespread and robust pathology, we find that human α-synuclein expression impairs autophagic flux in aging adult neurons. Genetic destabilization of the actin cytoskeleton rescues F-actin accumulation, promotes autophagosome clearance, normalizes the autophagolysosomal system, and rescues neurotoxicity in α-synuclein transgenic animals through an Arp2/3 dependent mechanism. Similarly, mitophagosomes accumulate in human α-synuclein-expressing neurons, and reversal of excessive actin stabilization promotes both clearance of these abnormal mitochondria-containing organelles and rescue of mitochondrial dysfunction. These results suggest that Arp2/3 dependent actin cytoskeleton stabilization mediates autophagic and mitophagic dysfunction and implicate failure of autophagosome maturation as a pathological mechanism in Parkinson's disease and related α-synucleinopathies.
ISSN:1553-7404
1553-7390
1553-7404
DOI:10.1371/JOURNAL.PGEN.1009359